Delta Np63 alpha regulates keratinocyte proliferation by controlling PTEN expression and localization

作者：Leonard M K; Kommagani R; Payal V; Mayo L D; Shamma H N; Kadakia M P^*

来源：Cell Death and Differentiation, 2011, 18(12): 1924-1933.

DOI：10.1038/cdd.2011.73

• p63
• PTEN
• Akt
• skin cancer
• keratinocytes

Delta Np63 alpha, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether Delta Np63 alpha regulates PTEN expression. Knockdown of Delta Np63 alpha led to increases in PTEN levels and loss of activated Akt, while overexpression of Delta Np63 alpha decreased PTEN levels and elevated active Akt. The repression of PTEN by Delta Np63 alpha occurs independently of p53 status, as loss of Delta Np63 alpha increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of Delta Np63 alpha resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where Delta Np63 alpha expression is highest. Additionally, we show that in keratinocytes a balance between Delta Np63 alpha and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased Delta Np63 alpha levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that Delta Np63 alpha negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and Delta Np63 alpha, which has an integral role in skin cancer development. Cell Death and Differentiation (2011) 18, 1924-1933; doi:10.1038/cdd.2011.73; published online 3 June 2011

• 出版日期2011-12